Cystic fibrosis (CF) is a life-threatening, heritable disease that results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR protein, which is located in the epithelium of various organs including the lungs, liver, pancreas, gastrointestinal tract, reproductive tract, and skin, is a cAMP-activated, ATP-gated ion channel that transports chloride and other ions across the epithelial cell membrane. In CF patients, defects in CFTR result in a reduction of chloride secretion, which in turn leads to a reduced fluid secretion due to solvent drag.
The hallmark symptoms of CF include the accumulation of thick, sticky mucus in various organs, particularly the lungs and pancreas. The presence of a thick mucus in the airways, including the lungs, nasal epithelium, and paranasal sinuses, results in impaired respiration, inflammation, and symptoms such as persistent coughing, wheezing, and shortness of breath. The thickened airway liquid also contributes to frequent infections and the development of diseases including pneumonia, bronchitis, and tuberculosis.
While management of CF has improved some over the years, options for treatment and care of CF patients remain limited. Specifically, there is a lack of effective means for inducing secretion in CF patients. As CF affects the lungs of most patients, a large part of the treatment routine involves clearing mucus from the airways, improving breathing, and preventing or ameliorating lung infection. Much of the treatment is accomplished through physical therapy.
Existing medications for improving respiratory function in CF patients include mucus-thinners, antibiotics, anti-inflammatory agents, and bronchodilators; furthermore, as lung function declines, lung transplantation might become necessary. There remains a need for development of additional and improved medicaments for CF. As will be clear from the following disclosures, these and other benefits are provided by the present invention.